Is FH p.Asp498= (c.1494C>T) pathogenic?

FH p.Asp498= (c.1494C>T) is classified Benign/Likely benign in FH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-14). Ultra-rare (popmax 0.0194%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Asp498= (c.1494C>T)?

FH p.Asp498= (c.1494C>T) is associated with hereditary neoplastic syndrome, hereditary leiomyomatosis and renal cell cancer (ClinVar).

How common is FH p.Asp498= (c.1494C>T) in the general population?

FH p.Asp498= (c.1494C>T) is ultra-rare (popmax 0.0194%, mid) (gnomAD).

FH p.Asp498=

c.1494C>T · rs199949526 · VCV1596396

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0194%, mid)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -4.8
Overall
CADD	5.807	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0194% Middle Eastern · 1/5,162 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00376%

Overall 0.000992% 16/1,612,354 alleles · ultra-rare exomes 16/1,460,368 · genomes 0/151,986 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0194%	5,162
South Asian	0.00989%	10,111
Remaining individualsnot grpmax-eligible	0.00321%	31,189
European (non-Finnish)	0.000339%	294,934

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FH
Protein: p.Asp498=
Coding: c.1494C>T
MANE Select: NM_000143
dbSNP: rs199949526
Type: single nucleotide variant
Location: chr1:241497867 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB
Residue 498: an α-helix

Full FH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary leiomyomatosis and renal cell cancer

Similar variants

FH p.Asp498Glu Uncertain significance ★★ ⚠ same residue
FH p.Asp498Gly Uncertain significance ★★ ⚠ same residue
FH c.1108+1G>A Pathogenic ★★ same condition
FH c.1108+1G>T Pathogenic/Likely pathogenic ★★ same condition
FH c.1236+1G>A Pathogenic/Likely pathogenic ★★ same condition
FH c.1236+1G>C Pathogenic ★★ same condition
FH c.1236+2T>G Pathogenic ★★ same condition
FH c.1237-1G>T Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/fh-p-asp498 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown